Methods and apparatus for treating anaphylaxis using electrical modulation

ABSTRACT

Methods and devices for treating anaphylaxis, anaphylactic shock, bronchial constriction, and/or asthma include providing an electrical impulse to a selected region of the vagus nerve of a patient suffering from anaphylaxis to block and/or modulate nerve signals that would regulate the function of, for example, myocardial tissue, vasodilation/constriction and/or pulmonary tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/772,361, filed Feb. 10, 2006, the entire disclosureof which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to the field of delivery of electricalimpulses to bodily tissues for therapeutic purposes, and morespecifically to devices and methods for treating conditions associatedwith shock, such as anaphylaxis by blocking and/or modulating signals inthe vagus nerve.

There are a number of treatments for various infirmities that requirethe destruction of otherwise healthy tissue in order to affect abeneficial effect. Malfunctioning tissue is identified, and thenlesioned or otherwise compromised in order to affect a beneficialoutcome, rather than attempting to repair the tissue to its normalfunctionality. While there are a variety of different techniques andmechanisms that have been designed to focus lesioning directly onto thetarget nerve tissue, collateral damage is inevitable.

Still other treatments for malfunctioning tissue can be medicinal innature, in many cases leaving patients to become dependent uponartificially synthesized chemicals. Examples of this are anti-asthmadrugs such as albuterol, proton pump inhibitors such as omeprazole(Prilosec), spastic bladder relievers such as Ditropan, and cholesterolreducing drugs like Lipitor and Zocor. In many cases, these medicinalapproaches have side effects that are either unknown or quitesignificant, for example, at least one popular diet pill of the late1990's was subsequently found to cause heart attacks and strokes.

Unfortunately, the beneficial outcomes of surgery and medicines are,therefore, often realized at the cost of function of other tissues, orrisks of side effects.

The use of electrical stimulation for treatment of medical conditionshas been well known in the art for nearly two thousand years. It hasbeen recognized that electrical stimulation of the brain and/or theperipheral nervous system and/or direct stimulation of themalfunctioning tissue, which stimulation is generally a whollyreversible and non-destructive treatment, holds significant promise forthe treatment of many ailments.

Electrical stimulation of the brain with implanted electrodes has beenapproved for use in the treatment of various conditions, including painand movement disorders including essential tremor and Parkinson'sdisease. The principle behind these approaches involves disruption andmodulation of hyperactive neuronal circuit transmission at specificsites in the brain. As compared with the very dangerous lesioningprocedures in which the portions of the brain that are behavingpathologically are physically destroyed, electrical stimulation isachieved by implanting electrodes at these sites to, first senseaberrant electrical signals and then to send electrical pulses tolocally disrupt the pathological neuronal transmission, driving it backinto the normal range of activity. These electrical stimulationprocedures, while invasive, are generally conducted with the patientconscious and a participant in the surgery.

Brain stimulation, and deep brain stimulation in particular, is notwithout some drawbacks. The procedure requires penetrating the skull,and inserting an electrode into the brain matter using a catheter-shapedlead, or the like. While monitoring the patient's condition (such astremor activity, etc.), the position of the electrode is adjusted toachieve significant therapeutic potential. Next, adjustments are made tothe electrical stimulus signals, such as frequency, periodicity,voltage, current, etc., again to achieve therapeutic results. Theelectrode is then permanently implanted and wires are directed from theelectrode to the site of a surgically implanted pacemaker. The pacemakerprovides the electrical stimulus signals to the electrode to maintainthe therapeutic effect. While the therapeutic results of deep brainstimulation are promising, there are significant complications thatarise from the implantation procedure, including stroke induced bydamage to surrounding tissues and the neurovasculature.

One of the most successful modern applications of this basicunderstanding of the relationship between muscle and nerves is thecardiac pacemaker. Although its roots extend back into the 1800's, itwas not until 1950 that the first practical, albeit external and bulkypacemaker was developed. Dr. Rune Elqvist developed the first trulyfunctional, wearable pacemaker in 1957. Shortly thereafter, in 1960, thefirst fully implanted pacemaker was developed.

Around this time, it was also found that the electrical leads could beconnected to the heart through veins, which eliminated the need to openthe chest cavity and attach the lead to the heart wall. In 1975 theintroduction of the lithium-iodide battery prolonged the battery life ofa pacemaker from a few months to more than a decade. The modernpacemaker can treat a variety of different signaling pathologies in thecardiac muscle, and can serve as a defibrillator as well (see U.S. Pat.No. 6,738,667 to Deno, et al., the disclosure of which is incorporatedherein by reference).

Anaphylaxis is a severe allergic reaction that occurs when the body isexposed to a substance to which it was previously sensitized. Thereaction causes a sudden release of chemicals, including histamines,from cells in the body's tissues. These chemicals dilate the bloodvessels, lowering blood pressure, and cause the blood vessels to leakfluid. The chemicals also act on the lungs, causing the airways toconstrict which makes breathing very difficult.

In some cases, anaphylaxis is mild, causing only hives and itching;however, anaphylaxis can be deadly. In anaphylactic shock, the mostsevere form of anaphylaxis, blood pressure drops severely and bronchialtissues swell dramatically. This causes the person to choke andcollapse. Anaphylactic shock is fatal if not treated immediately andcauses more than eight thousand deaths per year in the United Statesalone. The triggers for these fatal reactions range from exposure tonuts, insect stings, medication, etc. However, the triggers are mediatedby a series of hypersensitivity responses that result in uncontrollabledrop in blood pressure and airway occlusion driven by smooth muscleconstriction.

Given the common mediators of both asthmatic and anaphylacticbronchoconstriction, it is not surprising that asthma sufferers are at aparticular risk for anaphylaxis. Still, estimates place the numbers ofpeople who are susceptible to such responses at more than 40 million inthe United States alone. Tragically, many of these patients are fullyaware of the severity of their condition, and die while struggling invain to manage the attack medically. Many of these incidents occur inhospitals or in ambulances, in the presence of highly trained medicalpersonnel who are powerless to break the cycle of hypotension andbronchoconstriction affecting their patient. Typically, the severity andrapid onset of anaphylactic reactions does not render the pathology tochronic treatment, but requires more immediately acting medications.Among the most popular medications for treating anaphylaxis isepinephrine, commonly marketed in so-called “Epi-pen” formulations andadministering devices, which potential sufferers carry with them at alltimes. In addition to serving as an extreme bronchodilator, epinephrineraises the patient's heart rate dramatically, and can result intachycardia and heart attacks.

The smooth muscles that line the bronchial passages are controlled by aconfluence of vagus and sympathetic nerve fiber plexuses. Spasms of thebronchi during asthma attacks and anaphylactic shock can often bedirectly related to pathological signaling within these plexuses.Anaphylactic shock and asthma are major health concerns.

Asthma, and other airway occluding disorders resulting from inflammatoryresponses and inflammation-mediated bronchoconstriction, affects anestimated eight to thirteen million adults and children in the UnitedStates. A significant subclass of asthmatics suffers from severe asthma.An estimated 5,000 persons die every year in the United States as aresult of asthma attacks. Up to twenty percent of the populations ofsome countries are affected by asthma, estimated at more than a hundredmillion people worldwide. Asthma's associated morbidity and mortalityare rising in most countries despite increasing use of anti-asthmadrugs.

Asthma is characterized as a chronic inflammatory condition of theairways. Typical symptoms are coughing, wheezing, tightness of the chestand shortness of breath. Asthma is a result of increased sensitivity toforeign bodies such as pollen, dust mites and cigarette smoke. The body,in effect, overreacts to the presence of these foreign bodies in theairways. As part of the asthmatic reaction, an increase in mucousproduction is often triggered, exacerbating airway restriction. Smoothmuscle surrounding the airways goes into spasm, resulting inconstriction of airways. The airways also become inflamed. Over time,this inflammation can lead to scarring of the airways and a furtherreduction in airflow. This inflammation leads to the airways becomingmore irritable, which may cause an increase in coughing and increasedsusceptibility to asthma episodes.

Two medicinal strategies exist for treating this problem for patientswith asthma. The condition is typically managed by means of inhaledmedications that are taken after the onset of symptoms, or by injectedand/or oral medication that are taken chronically. The medicationstypically fall into two categories; those that treat the inflammation,and those that treat the smooth muscle constriction. The first is toprovide anti-inflammatory medications, like steroids, to treat theairway tissue, reducing its tendency to over-release of the moleculesthat mediate the inflammatory process. The second strategy is to providea smooth muscle relaxant (an anti-cholinergic and/or anti-adrenergicmedication) to reduce the ability of the muscles to constrict.

It has been highly preferred that patients rely on avoidance of triggersand anti-inflammatory medications, rather than on the bronchodilators astheir first line of treatment. For some patients, however, thesemedications, and even the bronchodilators are insufficient to stop theconstriction of their bronchial passages, and more than five thousandpeople suffocate and die every year as a result of asthma attacks.

Myocardial dysfunction involves a decrease in overall myocardialperformance. The determinants of myocardial performance are heart rate,preload, afterload, and contractility. Heart rate is a term used todescribe the frequency of the cardiac cycle, usually in number of numberof contractions of the heart (heart beats) per minute. The heartcontains two natural cardiac pacemakers that spontaneously cause theheart to beat. These can be controlled by the autonomic nervous systemand circulating adrenaline.

The body can increase the heart rate in response to a wide variety ofconditions in order to increase the cardiac output (the amount of bloodejected by the heart per unit time). Exercise, environmental stressorsor psychological stress can cause the heart rate to increase above theresting rate. The pulse is the most straightforward way of measuring theheart rate, but it can be deceptive when some strokes do not lead tomuch cardiac output. In these cases (as happens in some arrhythmias),the heart rate may be considerably higher than the pulse.

Preload is theoretically most accurately described as the initialstretching of cardiac myocytes prior to contraction. Preload is thevolume of blood present in a ventricle of the heart, after passivefilling and atrial contraction. Preload is affected by venous bloodpressure and the rate of venous return. These are affected by venoustone and volume of circulating blood.

Afterload is the tension produced by a chamber of the heart in order tocontract. Afterload can also be described as the pressure that thechamber of the heart has to generate in order to eject blood out of thechamber. In the case of the left ventricle, the afterload is aconsequence of the blood pressure, since the pressure in the ventriclemust be greater than the blood pressure in order to open the aorticvalve. For instance, hypertension (increased blood pressure) increasesthe left ventricular afterload because the left ventricle has to workharder to eject blood into the aorta. This is because the aortic valvewon't open until the pressure generated in the left ventricle is higherthan the elevated blood pressure.

Contractility is the intrinsic ability of a cardiac muscle fiber tocontract at any given fiber length. If myocardial performance changeswhile preload, afterload and heart rate are all constant, then thechange in performance must be due to the change in contractility.Chemicals that affect contractility are called inotropic agents. Forexample drugs such as catecholamines (norepinephrine and epinephrine)that enhance contractility are considered to have a positive inotropiceffect. All factors that cause an increase in contractility work bycausing an increase in intracellular calcium concentration [Ca++] duringcontraction.

The concept of contractility was necessary to explain why someinterventions (e.g. an adrenaline infusion) could cause an increase inmyocardial performance even if, as could be shown in experiments, thepreload, afterload and heart rate were all held constant. Experimentalwork controlling the other factors was necessary because a change incontractility is generally not an isolated effect. For example, anincrease in sympathetic stimulation to the heart increases contractilityand heart rate. An increase in contractility tends to increase strokevolume and thus a secondary decrease in preload.

Blood pressure is the pressure exerted by the blood on the walls of theblood vessels. Unless indicated otherwise, blood pressure refers tosystemic arterial blood pressure, i.e., the pressure in the largearteries delivering blood to body parts other than the lungs, such asthe brachial artery (in the arm). The pressure of the blood in othervessels is lower than the arterial pressure. Blood pressure values areuniversally stated in millimetres of mercury (mm Hg), and are alwaysgiven relative to atmospheric pressure. For example, the absolutepressure of the blood in an artery with mean arterial pressure stated as100 mm Hg, on a day with atmospheric pressure of 760 mm Hg, is 860 mmHg.

The systolic pressure is defined as the peak pressure in the arteriesduring the cardiac cycle; the diastolic pressure is the lowest pressure(at the resting phase of the cardiac cycle). The mean arterial pressureand pulse pressure are other important quantities. Typical values for aresting, healthy adult are approximately 120 mm Hg systolic and 80 mm Hgdiastolic (written as 120/80 mm Hg), with large individual variations.These measures of blood pressure are not static, but undergo naturalvariations from one heartbeat to another or throughout the day (in acircadian rhythm); they also change in response to stress, nutritionalfactors, drugs, or disease.

An instance of the connection between the vagus nerve and blood pressureregulation may be found in U.S. Pat. No. 5,707,400 (“'400”), to Terry,et al., titled, “Treating refractory hypertension by nerve stimulation,”which is incorporated in its entirety by reference. Hypertension (higherthan normal blood pressure) and its converse, hypotension (lower thannormal blood pressure), largely comprise the two sides of the coin thatrepresents the problems relating to blood pressure. Issuing relating tohypotension, its causes and effects, are discussed also in U.S. PatentApplication No. 20050283197 A1, to Daum, et al., titled, “Systems andmethods for hypotension,” which is incorporated in its entirety byreference.

Blood pressure exceeding normal values is called arterial hypertension.It itself is only rarely an acute problem, with the seldom exception ofhypertensive crisis, such as severe hypertension with acute impairmentof an organ system (especially the central nervous system,cardiovascular system and/or the renal system) and the possibility ofirreversible organ-damage. However, because of its long-term indirecteffects (and also as an indicator of other problems) it is a seriousworry to physicians diagnosing it. Persistent hypertension is one of therisk factors for strokes, heart attacks, heart failure, arterialaneurysms, and is the second leading cause of chronic renal failureafter diabetes mellitus.

All level of blood pressure puts mechanical stress on the arterialwalls. Higher pressures increase heart workload and progression ofunhealthy tissue growth (atheroma) that develops within the walls ofarteries. The higher the pressure, the more stress that is present andthe more atheroma tend to progress and the heart muscle tends tothicken, enlarge and become weaker over time.

Blood pressure that is too low is known as hypotension. Low bloodpressure may be a sign of severe disease and requires more urgentmedical attention. When blood pressure and blood flow is very low, theperfusion of the brain may be critically decreased (i.e., the bloodsupply is not sufficient), causing lightheadedness, dizziness, weaknessand fainting.

Sometimes the blood pressure drops significantly when a patient standsup from sitting. This is known as orthostatic hypotension; gravityreduces the rate of blood return from the body veins below the heartback to the heart, thus reducing stroke volume and cardiac output. Whenpeople are healthy, they quickly constrict the veins below the heart andincrease their heart rate to minimize and compensate for the gravityeffect. This is done at a subconscious level via the autonomic nervoussystem. The system usually requires a few seconds to fully adjust and ifthe compensations are too slow or inadequate, the individual will sufferreduced blood flow to the brain, dizziness and potential blackout.Increases in G-loading, such as routinely experienced by supersonic jetpilots “pulling Gs”, greatly increases this effect. Repositioning thebody perpendicular to gravity largely eliminates the problem.

Hypotension often accompanies and complicates many other systemic healthproblems, such as anaphylaxis and sepsis, leading to anaphylactic shockand septic shock, making it more difficult to address the underlyinghealth problem. For example, U.S. Patent Application No. 20050065553,Ben Ezra, et al., titled, “Applications of vagal stimulation,” which isincorporated in its entirety by reference, proposes to a method to treata patient's sepsis by applying an appropriately configured current tothe vagus nerve. However, when accompanied with refractory arterialhypotension, sepsis becomes septic shock.

Septic shock is a serious medical condition causing such effects asmultiple organ failure and death in response to infection and sepsis.Its most common victims are children and the elderly, as their immunesystems cannot cope with the infection as well as those of full-grownadults, as well as immunocompromised individuals. The mortality ratefrom septic shock is approximately 50%. Other various shock conditionsinclude: systemic inflammatory response syndrome, toxic shock syndrome,adrenal insufficiency, and anaphylaxis.

A subclass of distributive shock, shock refers specifically to decreasedtissue perfusion resulting in end-organ dysfunction. Cytokines TNFα,IL-1β, IL-6 released in a large scale inflammatory response may resultin massive vasodilation, increased capillary permeability, decreasedsystemic vascular resistance, and hypotension. Hypotension reducestissue perfusion pressure, and thus tissue hypoxia ensues. Finally, inan attempt to offset decreased blood pressure, ventricular dilatationand myocardial dysfunction will occur.

Accordingly, there is a need in the art for new products and methods fortreating the immediate symptoms of anaphylaxis, anaphylactic shock,bronchial constriction, asthma, etc.

SUMMARY OF THE INVENTION

The present invention involves products and methods of treatment ofanaphylaxis utilizing an electrical signal that may be applied to thevagus nerve to temporarily block and/or modulate the signals in thevagus nerve. The present invention also encompasses treatment ofanaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc.

In one or more embodiments, the present invention contemplates methodsand apparatus for delivering one or more electrical impulses to at leastone selected region of the vagus nerve to block and/or modulate signalsto the muscle fibers of the heart facilitating contractility, the fiberssurrounding the cardiac tissue facilitating an increase in heartfunction (thereby raising blood pressure), and/or the muscle fiberssurrounding the bronchi (facilitating opening of airways).

It shall be understood that the activation of such impulses may bedirected manually by a patient suffering from anaphylaxis.

In one or more embodiments of the present invention, the impulses areapplied in a manner that relaxes the myocardium to reduce the baselinelevel of tonic contraction, effects vasoconstriction (or dilation), andin cases of some shock, relaxes the smooth muscle lining the bronchialpassages to relieve the spasms that occur, such as during anaphylacticshock. The impulses may be applied by positioning leads on the nervesthat control cardiac activity, and/or bronchial activity respectively,such as the superior and/or inferior cardiac branches, and/or theanterior and/or posterior bronchial branches, of the right and/or leftbranches of the vagus nerve, which join with fibers from the sympatheticnerve chain to form the anterior and posterior coronary and pulmonaryplexuses. Leads may be positioned above one or both of the cardiac andpulmonary branches of the vagus nerve to include a block and/ormodulation of both organs. It shall also be understood that leadlessimpulses as shown in the art may also be utilized for applying impulsesto the target regions.

The mechanisms by which the appropriate impulse is applied to theselected region of the vagus nerve can include positioning the distalends of an electrical lead or leads in the vicinity of the nervoustissue controlling the myocardium, vessels of the heart (e.g., to affectvasoconstriction/dilation) and/or pulmonary muscles, which leads arecoupled to an implantable or external electrical impulse generatingdevice. The electric field generated at the distal tip of the leadcreates a field of effect that permeates the target nerve fibers andcauses the blocking and/or modulating of signals to the subject muscles.

The application of electrical impulses, either to the vagus nerve or thefibers branching off the vagus nerve to the cardiac muscles and/or thebronchial muscles to modulate the parasympathetic tone in order to relaxthe body's reaction to anaphylaxis is more completely described in thefollowing detailed description of the invention, with reference to thedrawings provided herewith, and in claims appended hereto.

Other aspects, features, advantages, etc. will become apparent to oneskilled in the art when the description of the invention herein is takenin conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purposes of illustrating the various aspects of the invention,there are shown in the drawings forms that are presently preferred, itbeing understood, however, that the invention is not limited by or tothe precise data, methodologies, arrangements and instrumentalitiesshown, but rather only by the claims of an issued utility application.

FIG. 1 is a diagrammatic view of the sympathetic and parasympatheticnerve systems;

FIG. 2 is a cross-sectional anatomical illustration of selected portionsof a neck, thoracic and abdominal region;

FIG. 3 illustrates a simplified view of the vagus nerve shown in FIGS. 1and 2;

FIG. 4 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulse applied to a portion or portions ofthe vagus nerve in accordance with an embodiment of the presentinvention; and

FIGS. 5-7 graphically illustrate experimental data obtained inaccordance with multiple embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

It shall be understood that the embodiments disclosed herein arerepresentative of preferred aspects of the invention and are so providedas examples of the invention. The scope of the invention, however, shallnot be limited to the disclosures provided herein, nor by theprovisional claims appended hereto.

While the exact physiological causes of anaphylaxis (e.g., inducingbronchial constriction and/or hypotension) have not been determined, thepresent invention postulates that the direct mediation of the smoothmuscle constriction is the result of over-activity in the vagus nerve,which is a response to the flood of pro-inflammatory mediators'interacting with the receptors on the nerve fibers themselves.

It has been observed in the literature that the nervous system maintainsa balance of the signals carried by the sympathetic and parasympatheticnerves. The vagus nerve, as the source of the signal to constrictbronchial smooth muscle and/or the cardiac muscle, is thought to providea baseline level of tonicity in the smooth muscles surrounding thebronchial passages and cardiac muscle, in order to: (i) prevent thetissue lining the airways from collapsing shut; and/or (ii) to preventtissue from expanding too much and depressing blood pressure.

Specifically, one or more embodiments of the present invention considerthe signals carried by the vagus (parasympathetic) nerve to cause: (i) aconstriction of the smooth muscle surrounding the bronchial passages,and/or (ii) a slowing of the heart. The sympathetic nerve fibers carrythe opposing signals that tend to open the bronchial passages as well asspeed up the heart rate. It should be recognized that the signals of thevagus nerve mediate a response similar to that of histamine, while thesympathetic signals generate an effect similar to epinephrine. Given thepostulated balance between the parasympathetic and sympathetic signals,removing the parasympathetic signal should create an imbalanceemphasizing the sympathetic signal. Along these lines, scientificliterature also indicates that severing the vagus nerve in dogs willraise the animals' heart rates, as well as open the bronchial passages,much the same way that epinephrine does.

Now referring to FIGS. 1 and 2, the vagus nerve is shown in more detail.The vagus nerve is composed of motor and sensory fibers. The vagus nerveleaves the cranium and is contained in the same sheath of dura matterwith the accessory nerve. The vagus nerve passes down the neck withinthe carotid sheath to the root of the neck. The branches of distributionof the vagus nerve include, among others, the superior cardiac, theinferior cardiac, the anterior bronchial and the posterior bronchialbranches. On the right side, the vagus nerve descends by the trachea tothe back of the root of the lung, where it spreads out in the posteriorpulmonary plexus. On the left side, the vagus nerve enters the thorax,crosses the left side of the arch of the aorta, and descends behind theroot of the left lung, forming the posterior pulmonary plexus.

In mammals, two vagal components have evolved in the brainstem toregulate peripheral parasympathetic functions. The dorsal vagal complex(DVC), consisting of the dorsal motor nucleus (DMNX) and itsconnections, controls parasympathetic function below the level of thediaphragm, while the ventral vagal complex (VVC), comprised of nucleusambiguus and nucleus retrofacial, controls functions above the diaphragmin organs such as the heart, thymus and lungs, as well as other glandsand tissues of the neck and upper chest, and specialized muscles such asthose of the esophageal complex.

The parasympathetic portion of the vagus innervates ganglionic neuronswhich are located in or adjacent to each target organ. The VVC appearsonly in mammals and is associated with positive as well as negativeregulation of heart rate, bronchial constriction, vocalization andcontraction of the facial muscles in relation to emotional states.Generally speaking, this portion of the vagus nerve regulatesparasympathetic tone. The VVC inhibition is released (turned off) instates of alertness. This in turn causes cardiac vagal tone to decreaseand airways to open, to support responses to environmental challenges.

The parasympathetic tone is balanced in part by sympathetic innervation,which generally speaking supplies signals tending to expand themyocardium, affect vasoconstriction, and/or to relax the bronchialmuscles, so that over-contraction and over-constriction, respectively,do not occur. Overall, myocardium tone, vasodilation, and/or airwaysmooth muscle tone are dependent on several factors, includingparasympathetic input, inhibitory influence of circulating epinephrine,NANC inhibitory nerves and sympathetic innervation of theparasympathetic ganglia. Stimulation of the vagus nerve (up-regulationof tone), such as may occur in shock, results in a heart rate decreaseand airway constriction. In this context, up-regulation is the processby which the specific effect is increased, whereas down-regulationinvolves a decrease of the effect. In general, the pathology of shockappears to be mediated by inflammatory cytokines that overwhelmreceptors on the nerve cells and cause the cells to massivelyup-regulate the parasympathetic tone. On a cellular level, up-regulationis the process by which a cell increases the number of receptors to agiven hormone or neurotransmitter to improve its sensitivity to thismolecule. A decrease of receptors is called down-regulation.

Anaphylaxis appears to be mediated predominantly by the hypersensitivityto an allergen causing the massive overproduction of cholenergicreceptor activating cytokines that overdrive the otherwise normallyoperating vagus nerve to signal massive constriction of the airways.

In the case of asthma (which may be related to anaphylaxis), it appearsthat the airway tissue has both (i) a hypersensitivity to the allergenthat causes the overproduction of the cytokines that stimulate thecholenergic receptors of the nerves and/or (ii) a baseline highparasympathetic tone or a high ramp up to a strong parasympathetic tonewhen confronted with any level of cholenergic cytokine. The combinationcan be lethal.

Sepsis is mediated by severe infection and may result in a large scaleinflammatory response that releases cytokines TNFα, IL-1β, IL-6mediating massive vasodilation, increased capillary permeability,decreased systemic vascular resistance, and hypotension. By comparison,anaphylaxis appears to be mediated predominantly by the hypersensitivityto an allergen causing the massive overproduction of cholenergicreceptor activating cytokines that overdrive the otherwise normallyoperating vagus nerve to signal massive constriction of the airways.Drugs such as epinephrine drive heart rate up while also relaxing thebronchial muscles, effecting temporary relief of symptoms from theseconditions.

Drugs such as epinephrine drive heart rate up while also relaxing thebronchial muscles, effecting temporary relief of symptoms from theseconditions. As mentioned above, experience has shown that severing thevagus nerve (an extreme version of reducing the parasympathetic tone)has an effect similar to that of epinephrine and adrenaline on heartrate and bronchial diameter in that the heart begins to race(tachycardia) and the bronchial passageways dilate.

In accordance with at least one aspect of the present invention, thedelivery, in a patient suffering from anaphylaxis, anaphylactic shock,bronchial constriction, asthma, etc., an electrical impulse sufficientto block and/or modulate transmission of signals along the vagus nervewill result in relaxation of the bronchi smooth muscle, dilatingairways, raising the heart function (and thus the blood pressure),and/or counteract the effect of anaphylaxis and/or histamine on thevagus nerve. Depending on the placement of the impulse, the signalblocking and/or modulation can also raise the heart function.

In accordance with at least one aspect of the present invention,blocking and/or modulating the signal in the vagus nerve, and/orblocking and/or affecting the anaphylaxis or histamine response of thevagus nerve, to reduce parasympathetic tone provides an immediateemergency response, much like a defibrillator, in situations ofanaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc.,providing immediate temporary dilation of the airways and/or an increaseof heart function until subsequent measures, such as administration ofmedication, rescue breathing and intubation can be employed. Moreover,the teachings of the present invention permit immediate airway dilationand/or heart function increase to enable subsequent life saving measuresthat otherwise would be ineffective or impossible due to severeconstriction or other physiological effects. Treatment in accordancewith the present invention provides bronchodilation and/or increasedheart function for a long enough period of time so that administeredmedication (such as epinephrine) has time to take effect before thepatient suffocates.

The methods described herein of applying an electrical impulse to aselected region of the vagus nerve may further be refined such that theat least one region may comprise at least one nerve fiber emanating fromthe patient's tenth cranial nerve (the vagus nerve), and in particular,at least one of the anterior bronchial branches thereof, at least one ofthe posterior bronchial branches thereof, at least one of the superiorcardiac branches thereof, and/or at least one of the inferior cardiacbranches thereof. Preferably the impulse is provided to at least one ofthe anterior pulmonary or posterior pulmonary plexuses aligned along theexterior of the lung. As necessary, the impulse may be directed tonerves innervating only the bronchial tree and lung tissue itself. Inaddition, the impulse may be directed to a region of the vagus nerve toblock and/or modulate one or both of the cardiac and bronchial branches.As recognized by those having skill in the art, this embodiment shouldbe carefully evaluated prior to use in patients known to havepreexisting cardiac issues.

With respect to the cardiac branches, the cardiac plexus is situated atthe base of the heart, and is divided into a superficial part, whichlies in the concavity of the aortic arch, and a deep part, between theaortic arch and the trachea. The two parts are, however, closelyconnected. The superficial part of the cardiac plexus lies beneath thearch of the aorta, in front of the right pulmonary artery. It is formedby the superior cardiac branch of the left sympathetic nerve and thelower superior cervical cardiac branch of the left vagus. Thesuperficial part of the cardiac plexus gives branches (a) to the deeppart of the plexus; (b) to the anterior coronary plexus; and (c) to theleft anterior pulmonary plexus. The deep part of the cardiac plexus issituated in front of the bifurcation of the trachea, above the point ofdivision of the pulmonary artery, and behind the aortic arch. It isformed by the cardiac nerves derived from the cervical ganglia of thesympathetic, and the cardiac branches of the vagus and recurrent nerves.The only cardiac nerves which do not enter into the formation of thedeep part of the cardiac plexus are the superior cardiac nerve of theleft sympathetic nerve, and the lower of the two superior cervicalcardiac branches from the left vagus, which pass to the superficial partof the plexus.

Further reference is now made to FIG. 3, which illustrates a simplifiedview of the vagus nerve shown in FIG. 2 and cardiac and pulmonarybranches thereof. Also shown is a vagus nerve stimulation (VNS) device300 for stimulation of the vagus nerve. VNS device 300 is intended forthe treatment of anaphylaxis, anaphylactic shock, bronchialconstriction, asthma, hypotension, etc. VNS device 300 may include anelectrical impulse generator 310; a power source 320 coupled to theelectrical impulse generator 310; a control unit 330 in communicationwith the electrical impulse generator 310 and coupled to the powersource 320; and electrodes 340 coupled to the electrical impulsegenerator 310 for attachment via leads 350 to one or more selectedregions 200A, 200B of a vagus nerve 200 of a mammal. The control unit330 may control the electrical impulse generator 310 for generation of asignal suitable for amelioration of, for example, the bronchialconstriction or hypotension when the signal is applied via theelectrodes 340 to the vagus nerve 200. It is noted that VNS device 300may be referred to by its function as a pulse generator.

In accordance with one embodiment, one or more electrical impulses aredirected to location A on or near the vagus nerve above the cardiacbranch. In this embodiment one or more electrical impulses areintroduced at the location A to block and/or modulate and/or inhibitup-regulation of the parasympathetic tone and effect a dilation ofairways and increase in heart function.

In accordance with another embodiment, one or more electrical impulsesare directed to location B on or near the vagus nerve below the cardiacbranch proximal to the pulmonary branch. In this embodiment one or moreelectrical impulses are introduced at the location B to block and/ormodulate and/or inhibit up-regulation of the parasympathetic tone toeffect only a dilation of airways.

In patients known to be subject to anaphylactic shock or severe asthmaattacks, one or more electrical impulse emitting devices 300 may beimplanted in one or more selected regions 200A, 200B of the vagus nerve200. Device 300 may be percutaneous for emergency applications, whereindevice 300 may comprise an electrode 340 powered via an external powersource 320.

U.S. Patent Application Publications 2005/0075701 and 2005/0075702, bothto Shafer, both of which are incorporated herein by reference, relatingto stimulation of neurons of the sympathetic nervous system to attenuatean immune response, contain descriptions of pulse generators that may beapplicable to the present invention.

FIG. 4 illustrates an exemplary electrical voltage/current profile for ablocking and/or modulating impulse applied to a portion or portions ofthe vagus nerve in accordance with an embodiment of the presentinvention. A suitable electrical voltage/current profile 400 for theblocking and/or modulating impulse 410 to the portion or portions 200A,200B of the vagus nerve 200 may be achieved using a pulse generator 310.In a preferred embodiment, the pulse generator 310 may be implementedusing a power source 320 and a control unit 330 having, for instance, aprocessor, a clock, a memory, etc., to produce a pulse train 420 to theelectrode(s) 340 that deliver the blocking and/or modulating impulse 410to the nerve 200 via leads 350. For percutaneous use, the VNS device 300may be available to the surgeon as external emergency equipment. Forsubcutaneous use, the VNS device 300 may be surgically implanted, suchas in a subcutaneous pocket of the abdomen. The VNS device 300 may bepowered and/or recharged from outside the body or may have its own powersource 320. By way of example, the VNS device 300 may be purchasedcommercially. The VNS device 300 is preferably programmed with aphysician programmer, such as a Model 7432 also available fromMedtronic, Inc.

The parameters of the modulation signal 400 are preferably programmable,such as the frequency, amplitude, duty cycle, pulse width, pulse shape,etc. In the case of an implanted pulse generator, programming may takeplace before or after implantation. For example, an implanted pulsegenerator may have an external device for communication of settings tothe generator. An external communication device may modify the pulsegenerator programming to improve treatment.

The electrical leads 350 and electrodes 340 are preferably selected toachieve respective impedances permitting a peak pulse voltage in therange from about 0.2 volts to about 20 volts.

The blocking and/or modulating impulse signal 410 preferably has afrequency, an amplitude, a duty cycle, a pulse width, a pulse shape,etc. selected to influence the therapeutic result, namely blockingand/or modulating some or all of the vagus nerve transmissions. Forexample the frequency may be about 1 Hz or greater, such as betweenabout 25 Hz to 3000 Hz, or between about 1000 Hz to about 2500 Hz.(These are notably higher frequencies than typical nerve stimulation ormodulation frequencies.) The modulation signal may have a pulse widthselected to influence the therapeutic result, such as about 20 μS orgreater, such as about 20 μS to about 1000 μS. The modulation signal mayhave a peak voltage amplitude selected to influence the therapeuticresult, such as about 0.2 volts or greater, such as about 0.2 volts toabout 20 volts.

In accordance with a preferred embodiment, VNS devices 300 in accordancewith the present invention are provided in the form of a percutaneous orsubcutaneous implant that can be reused by an individual.

In accordance with another embodiment, devices in accordance with thepresent invention are provided in a “pacemaker” type form, in whichelectrical impulses 410 are generated to a selected region 200A, 200B ofthe vagus nerve 200 by VNS device 300 on an intermittent basis to createin the patient a lower reactivity of the vagus nerve 200 toup-regulation signals.

In accordance with another embodiment, devices 300 in accordance withthe present invention are incorporated in an endotracheal tube device toameliorate bronchospasm during surgery. In a preferred embodiment one ormore devices 300 are located in the distal portion of an endotrachealtube to contact selected regions 200A, 200B of the vagus nerve 200 toimpart appropriate electrical impulses to dampen reactivity of the vagusnerve 200 to stimulus. In all cases of permanent implantation, however,the implanting surgeon should vary the signal modulated by the controlunit 330 and specific location of the lead 350 until the desired outcomeis achieved, and should monitor the long-term maintenance of this effectto ensure that adaptive mechanisms in the patient's body do not nullifythe intended effects.

In addition, or as an alternative to the devices to implement themodulation unit for producing the electrical voltage/current profile ofthe blocking and/or modulating impulse to the electrodes, the devicedisclosed in U.S. Patent Publication No.: 2005/0216062 (the entiredisclosure of which is incorporated herein by reference), may beemployed. U.S. Patent Publication No.: 2005/0216062 discloses amulti-functional electrical stimulation (ES) system adapted to yieldoutput signals for effecting faradic, electromagnetic or other forms ofelectrical stimulation for a broad spectrum of different biological andbiomedical applications. The system includes an ES signal stage having aselector coupled to a plurality of different signal generators, eachproducing a signal having a distinct shape such as a sine, a square or asaw-tooth wave, or simple or complex pulse, the parameters of which areadjustable in regard to amplitude, duration, repetition rate and othervariables. The signal from the selected generator in the ES stage is fedto at least one output stage where it is processed to produce a high orlow voltage or current output of a desired polarity whereby the outputstage is capable of yielding an electrical stimulation signalappropriate for its intended application. Also included in the system isa measuring stage which measures and displays the electrical stimulationsignal operating on the substance being treated as well as the outputsof various sensors which sense conditions prevailing in this substancewhereby the user of the system can manually adjust it or have itautomatically adjusted by feedback to provide an electrical stimulationsignal of whatever type he wishes and the user can then observe theeffect of this signal on a substance being treated.

Prior to discussing experimental results, a general approach to treatinganaphylaxis, anaphylactic shock, bronchial constriction, asthma,hypotension, etc., in accordance with one or more embodiments of theinvention may include applying at least one electrical impulse to one ormore selected regions of the vagus nerve of a mammal in need of relieffrom anaphylaxis.

The method may include: implanting one or more electrodes to theselected regions of the vagus nerve; and applying one or more electricalstimulation signals to the electrodes to produce the at least oneelectrical impulse, wherein the one or more electrical stimulationsignals are of a frequency between about 1 Hz to 3000 Hz, and anamplitude of between about 1-6 volts.

The one or more electrical stimulation signals may be of a frequencybetween about 750 Hz to 1250 Hz; or between about 10 Hz to 35 Hz. Theone or more electrical stimulation signals may be of an amplitude ofbetween about 0.75 to 1.5 volts, such as about 1.25 volts. The one ormore electrical stimulation signals may be one or more of a full orpartial sinusoid, square wave, rectangular wave, and/or triangle wave.The one or more electrical stimulation signals may have a pulsed on-timeof between about 50 to 500 microseconds, such as about 100, 200 or 400microseconds.

The polarity of the pulses may be maintained either positive ornegative. Alternatively, the polarity of the pulses may be positive forsome periods of the wave and negative for some other periods of thewave. By way of example, the polarity of the pulses may be altered aboutevery second.

While up-regulating the signal provided by the sympathetic nerves mayaccomplish the desired treatment effect, the present invention suggeststhat a more direct route to immediately breaking the cycle ofanaphylaxis, anaphylactic shock, bronchial constriction, asthma,hypotension, etc., is via the vagus nerve because the mode of action forthe hypersensitivity response is at the vagus nerve and not through thesympathetic nerves. Therefore, experiments were performed to identifyexemplary methods of how electrical signals can be supplied to theperipheral nerve fibers that innervate and/or control the bronchialsmooth muscle to (i) reduce the sensitivity of the muscle to the signalsto constrict, and (ii) to blunt the intensity of, or break theconstriction once it has been initiated. In addition, experiments wereperformed to identify exemplary methods of how electrical signals can besupplied to the peripheral nerve fibers that innervate and/or controlvasoconstriction/dilation, and/or that innervate and/or control themyocardium to (i) reduce the sensitivity of the muscle to the signals oftonic contraction, and (ii) to blunt the intensity of, or break thetonic over-contraction once it has been initiated.

In particular, specific signals, selected from within a range of knownnerve signals, were applied to the vagus nerves and/or the sympatheticnerves in guinea pigs, to produce selective interruption or reduction inthe effects of lung vagal nerve activity leading to attenuation ofanaphylaxis-induced bronchoconstriction and/or hypotension.

Experimentation

As opposed to experiments in which hypotension and/or bronchialconstriction is induced using i.v. histamine, the testing procedure andtest data below were obtained in response to anaphylaxis. Fifteen maleguinea pigs (400 g) were sensitized by the intraperitoneal injection ofovalbumin (10 mg/kg i.p. every 48 hrs for three doses). Three weekslater animals were transported to the lab and immediately anesthetizedwith an i.p. injection of urethane 1.5 g/kg. Skin over the anterior neckwas opened and the carotid artery and both jugular veins were cannulatedwith PE50 tubing to allow for blood pressure/heart rate monitoring anddrug administration, respectively. The trachea was cannulated and theanimal ventilated by positive pressure, constant volume ventilationfollowed by paralysis with succinylcholine (10 ug/kg/min) to paralyzedchest wall musculature to remove the contribution of chest wall rigidityfrom airway pressure measurements. Both vagus nerves were isolated andconnected to shielded electrodes to allow selective stimuli of thesenerves in the manner disclosed in the one or more embodiments disclosedabove. Following fifteen minutes of stabilization, baseline hemodynamicand airway pressure measurements were made before and after theadministration of increasing concentrations of ovalbumin (0.001-1.0mg/kg i.v.). Following the increase in airway pressure and hypotensionaccompanying the anaphylactic response, vagal nerve modulation was madeat variations of frequency, voltage and pulse duration to identityparameters that attenuate the hypotensive and bronchoconstrictiveresponses. Euthanasia was accomplished with intravenous potassiumchloride.

With reference to FIG. 5, the top line (BP) shows blood pressure, thesecond line shows airway pressure (AP1), the third line shows airwaypressure (AP2) on another sensor, the fourth line is the heart rate (HR)derived from the pulses in the blood pressure. As a baseline of theanaphylactic reaction that is achieved in this model, the first guineapig's response to the ovalbumin was recorded without any electricalstimulation. The graph in FIG. 20 shows the effect of an injection of0.75 mg of ovalbumin. About five minutes after the injection, the bloodpressure dropped from 125 to 50 mmHg while the airway pressure increasedfrom 11 to 14 cm H₂O. This effect was sustained for over sixty (60)minutes with the blood pressure showing some recovery to 90 mmHg.

With reference to FIG. 6, another animal (guinea pig #2) was tested todetermine the effect of the signals that were shown to be effective inthe histamine induced asthma model (Experimental Procedure 1 above).FIG. 21 demonstrates the effect of a 25 Hz, 200 uS, 1.25V square wavesignal applied simultaneously to both left and right vagus nerves insensitized guinea pig #2 after injection with 1.125 mg ovalbumin tocause an anaphylactic response. The larger dose was used to cause a moresevere reaction. Starting from the left side of the graph, it may beseen that before electrical stimulation, the blood pressure was severelydepressed at 30 mmHg while the airway pressure was almost 22 cm H₂O (9.5cm increase over baseline). The first peak in blood pressure coincideswith the electrical signal applied to the vagus—the blood pressureincreased to 60 mmHg (a 100% increase) while the airway pressure reducedby 6.5 cm to about 15.5 cm H₂O (a 68% reduction). The next peak showsthe effect repeated. The other peaks show the effects of changing thesignal voltage—lowering the voltage results in reduced effectiveness.

With reference to FIG. 7, the effect of changing the signal frequencyand pulse width on blood pressure and airway pressure is shown. Thefirst peak in blood pressure coincides with a 15 Hz, 300 uS, 1.25Velectrical signal applied to both sides of the vagus—the blood pressurewas increased to 60 mmHg (a 70% increase) while the airway pressure wasreduced by 1.5 cm to about 17 cm H₂O (a 25% reduction). The next peakdemonstrates a 10 Hz signal—the beneficial effects are reduced comparedto 15 Hz. The other peaks show the effects of changing the signalfrequency and pulse width—lowering the frequency below 15 Hz or loweringthe pulse width below 200 uS results in reduced effectiveness. Thesignals between 15-25 Hz, and 200-300 uS maintain about the sameeffectiveness in decreasing the hypotensive and bronchoconstrictivesymptoms of anaphylaxis.

Conclusions that may be drawn from the above experimental data include:(1) That the airway constriction and hypotension caused by anaphylaxisin guinea pigs can be significantly reduced by applying appropriateelectrical signals to the vagus nerve. (2) That signals from 15 Hz to 25Hz, 200 uS to 300 uS, and 1.0V to 1.5V were equally effective. (3) Thata 25 Hz, 200 μS, 1.25V signal applied to the vagus nerve, airwayconstriction due to anaphylaxis was reduced up to 68%. This effect hasbeen repeated on several animals. (4) That the 25 Hz, 200 uS, 1.25Vsignal applied to the vagus nerve produces up to a 100% increase inblood pressure in an anaphylactic guinea pig experiencing severehypotension. This effect has been repeated on several animals. This mayhave applications in the treatment of other low blood pressureconditions such as septic shock. (5) That there is some evidence thatthe application of the signal to the vagus nerve may have the ability toshorten the duration of an anaphylactic episode.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A method of treating anaphylaxis comprising applying at least oneelectrical impulse to at least one selected region of the vagus nerve ofa mammal in need of relief from anaphylaxis, such that an effect onregulation of at least one of muscle fibers of the mammal's cardiactissue, vasoconstriction, and the muscle fibers of the mammal's bronchiis achieved.
 2. The method set forth in claim 1 wherein the at least oneselected region comprises a region of the vagus nerve proximal to atleast one of the cardiac branch and the bronchial branch of the vagusnerve.
 3. The method set forth in claim 2 wherein the effect includes atleast one of: improving myocardium performance includes increasing heartfunction; increasing blood pressure; maintaining a stable heart rate;affecting vasoconstriction/dilation; increased opening of airways of thebronchi; and reduction in bronchial spasms.
 4. The method set forth inclaim 3 wherein at least one selected region of the vagus nerve includesone or more of: the superior and/or inferior cardiac branches of thevagus nerve; the anterior and/or posterior bronchial branches of thevagus nerve; the right branch of the vagus nerve, the left branch of thevagus nerve; at or near the anterior or posterior coronary plexus; andat or near the anterior or posterior pulmonary plexus.
 5. A device forthe treatment of anaphylaxis comprising: an electrical impulsegenerator; a power source coupled to the electrical impulse generator; acontrol unit in communication with the electrical impulse generator andcoupled to the power source; electrodes coupled to the electricalimpulse generator; and electrode leads coupled to the electrodes forattachment to one or more selected regions of a vagus nerve of a mammal;wherein the control unit is operable to modulate the electrical impulsegenerator for generation of a signal suitable for treatment of theanaphylaxis and/or related complications when the signal is applied viathe electrode leads to the vagus nerve.
 6. The device of claim 5,wherein the electrode leads have wide contact areas.
 7. A method oftreating anaphylaxis, anaphylactic shock, bronchial constriction, and/orasthma, comprising applying at least one electrical impulse to one ormore selected regions of the vagus nerve of a mammal in need of relief.8. The method of claim 7, further comprising: implanting one or moreelectrodes to the selected regions of the vagus nerve; and applying oneor more electrical stimulation signals to the electrodes to produce theat least one electrical impulse.
 9. The method of claim 8, wherein theone or more electrical stimulation signals are of a frequency betweenabout 1 Hz to 3000 Hz, and an amplitude of between about 1-6 volts. 10.The method of claim 9, wherein the one or more electrical stimulationsignals are of a frequency between about 750 Hz to 1250 Hz.
 11. Themethod of claim 9, wherein the one or more electrical stimulationsignals are of a frequency between about 10 Hz to 35 Hz.
 12. The methodof claim 9, wherein the one or more electrical stimulation signals areof an amplitude of between about 0.75 to 1.5 volts.
 13. The method ofclaim 9, wherein the one or more electrical stimulation signals are oneor more of a full or partial sinusoid, square wave, rectangular wave,triangle wave.
 14. The method of claim 9, wherein the one or moreelectrical stimulation signals have a pulsed on-time of between about 50to 500 microseconds.
 15. The method of claim 9, wherein the one or moreelectrical stimulation signals have a frequency of about 25 Hz, a pulsedon-time of about 200-400 microseconds, and an amplitude of about 1 volt.16. The method of claim 9, wherein the one or more electricalstimulation signals have a frequency of about 25 Hz, a pulsed on-time ofbetween about 100 to 400 microseconds, and an amplitude of about 1 volt.17. The method of claim 16, wherein the pulsed on-time is one of: about400 microseconds, about 200 microseconds, and about 100 microseconds.18. The method of claim 9, further comprising maintaining a polarity ofthe pulse either positive or negative.
 19. The method of claim 18,further comprising alternating the polarity of the pulse to be positivefor some periods of the wave and negative for some other periods of thewave.
 20. The method of claim 18, further comprising alternating thepolarity of the pulse about every second.